1. Field of the Invention
This invention relates to O.sup.2,2'-anhydro-1-(.beta.-D-arabinofuranosyl)-cytosine nucleosides and 1-(.beta.-D-arabinofuranosyl)-cytosine nucleosides and salts thereof and to methods of preparing such nucleosides and salts. In a further aspect this invention relates to methods of preparing salts of O.sup.2,2'-anhydro-1-(3'-O-acyl-5'-O-acyl-.beta.-D-arabinofuranosyl)-cytos ine nucleosides. In a still further aspect this invention relates to 3'-O-acyl- and 3'-O-acyl-5'-O-acyl- derivatives of 1-(.beta.-D-arabinofuranosyl)-cytosine nucleosides and salts thereof and methods of preparing such compounds and salts.
2. The Prior Art
The salts of O.sup.2,2'-anhydro-1-(.beta.-D-arabinofuranosyl)-cytosine and its 5-halo, 5-lower alkyl and 5-halo(alkyl)cytosine derivatives are known to the art (note, for example, Walwick et al. Proc. Chem. Soc., 84 (1959) and U.S. Pat. No. 3,463,850). However, because of the instability under even mild basic conditions of the parent compounds, and also the great insolubility of the salts in most inert organic solvents, these salts cannot be acylated at the 3'-position by conventional nucleoside acylation procedures. For example, treatment of the salts of O.sup.2,2'-anhydro-1-(.beta.-D-arabinofuranosyl)-cytosine and their derivatives, with even such mild bases as pyridine or aqueous pyridine or aqueous sodium bicarbonatecarbonate buffer, causes neutralization of the salt to give the unstable free base which decomposes with cleavage of the O.sup.2,2'-anhydro linkage. Also attempted acylation with acyl anhydrides in pyridine results in extensive decomposition. Accordingly, I have now discovered a process for preparing the salts of O.sup.2 ,2'-anhydro-1-(3',5'-di-O-acyl-.beta.-D-arabinofuranosyl)-cytosine(s) directly from the salts of the corresponding O.sup.2,2'-anhydro-1-(.beta.-D-arabinofuranosyl)-cytosines and 3'-O-acyl- derivatives thereof.
Similarly with respect to the 3',5'-di-O-acyl- derivatives, and particularly the 3'-O-acyl- derivatives of 1-(.beta.-D-arabinofuranosyl)-cytosines, these compounds could not be pragmatically made by conventional procedures. Here the problem is not one of stability, since the parent compounds are stable, but rather one of selectivity, since invariably conventional acylation procedures would result in preferential acylation of the more reactive free hydroxy at the 5'-position of the sugar moiety.
Thus selective acylation of the 5'-hydroxyl group of 1-(.beta.-D-arabinofuranosyl)-cytosine is quite feasible due to the greater reactivity of the primary hydroxy group relative to the secondary 2'- or 3'-hydroxyl functions. It is also presumably possible to obtain 1-(2',3'-di-O-acyl-.beta.-D-arabinofuranosyl)-cytosine via initial blocking of the more reactive 5'-hydroxyl group with an acid labile substituent such as the trityl group (see e.g., J. Med. Chem., 10, 762 (1967) for the preparation of 1-(5'-O-trityl-.beta.-D-arabinofuranosyl)-cytosine). There is, however, no apparent difference in reactivity between the 2'- and 3'-hydroxyl groups of arabinofuranosyl nucleosides and accordingly there is no selective way for preparing either 1-(3'-O-acyl-.beta.-D-arabinofuranosyl)-cytosines or 1-(3',5'-di-O-acyl-.beta.-D-arabinofuranosyl)-cytosines containing unsubstituted 2'-hydroxy functions. There is also no opportunity presently available for preparing arabinofuranosyl cytosines containing suitable removable protecting groups specifically at the 2'- or 3'-positions. Thus there is no way presently available to selectively acylate 1-(.beta.-D-arabinofuranosyl)-cytosines at the 3'-O-position nor is there a suitable 2'-O-protecting group available which would enable one to first selectively protect the 2'-O-position and then acylate the 3'-O-position or the 3',5'-positions. In addition it must be borne in mind that conventional acylation of cytosine nucleosides leads to acylation of both free hydroxyl functions and of the amino group on the cytosine ring. Such N.sup.4 -acyl derivatives of 1-(.beta.-D-arabinofuranosyl)-cytosines have been found to possess no biological activity. Accordingly, I have discovered a method of preparing 3'-O-acyl- and 3',5'-di-O-acyl- derivatives of 1-(.beta.-D-arabinofuranosyl)-cytosines by selectively cleaving the O.sup.2,2'-anhydro linkage of the corresponding O.sup.2,2'-anhydro-1-(.beta.-D-arabinofuranosyl)-cytosine without cleavage of the 3'-O- and/or 5'-O-acyl- groups to yield the corresponding 3'-O-acyl- or 3',5'-di-O-acyl- derivatives of 1-(.beta.-D-arabinofuranosyl)-cytosine nucleosides.